Association of antagonists of the vasopressin receptor and calcimimetics, composition and use thereof for the treatment of polycystic kidney

a technology of vasopressin receptor and calcimimetics, which is applied in the direction of drug compositions, medical preparations, urinary disorders, etc., can solve the problems of kidney failure, glomerular filtration problems, and compromise the normal kidney function

Inactive Publication Date: 2019-05-09
UNIV DEGLI STUDI DI BARI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0036]The surprising effect of the combination of the invention is due to the synergy of the individual components of the combination, i.e. the one or more antagonists of the vasopressin receptor and the one or more calciomimetics. In fact, as it will be shown in the Experimental Section, they act on two different alterations that are found in the renal cells of the patients affected by polycystic kidney, thus re-establishing the physiological condition.

Problems solved by technology

In particular, the autosomal dominant form (ADPKD) is the most common lethal genetic disease and is the first cause of kidney failure worldwide.
The formation of the cysts compromises the normal kidney function, giving glomerular filtration problems, urine concentration and excretion of the same.
At present there is no pharmacological cure for the disease.
The treatment with the cyclin kinase inhibitors, and in particular with roscovitine, causes heavy side effects.
The mTOR inhibitors, on the long term, cause nephrotoxicity.
However, the calciomimetics have the side effect of hypocalcemia, that in turn can induce psychic disorders of various kinds, arrhythmias, muscle spasms, convulsions, etc. in the patient.

Method used

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  • Association of antagonists of the vasopressin receptor and calcimimetics, composition and use thereof for the treatment of polycystic kidney
  • Association of antagonists of the vasopressin receptor and calcimimetics, composition and use thereof for the treatment of polycystic kidney
  • Association of antagonists of the vasopressin receptor and calcimimetics, composition and use thereof for the treatment of polycystic kidney

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0050]ciPTE-PC1KO Cellular Model

[0051]Calibration experiments of the intracellular calcium levels (FIG. 1), that have demonstrated that under basal conditions the ciPTEC-PC1KO cells, in which the polycystin 1 has been stably silenced, have calcium levels that are significantly lower than the ciPTECwt cells isolated from healthy subjects (93.4 nM vs. 113.4 nM, P=0.0004), have been carried out. Therefore, the ciPTEC-PC1KO cells are a valid model of human kidney cells of the proximal tubule of patients suffering from ADPKD.

example 2

[0052]Presence of CaSR on ciPTECwt, ciPTEC-PC1KO and ciPTEC-PC1Pt Cells

[0053]Calciomimetics conventionally act on the CaSR membrane receptor present on some cellular types, for example on the parathyroid cells, by sensitizing such a receptor in the presence of extracellular calcium ions.

[0054]The expression by the ciPTECwt, ciPTEC-PC1KO and ciPTEC-PC1Pt cellular lines of CaSR has been verified through Western Blotting. From FIG. 2, it can be noted that all of the cellular lines isolated from healthy subjects (ciPTECwt), the cells isolated from patients affected by ADPKD (ciPTEC-PC1Pt) and the ciPTEC-PC1KO cells, endogenously express the CaSR receptor.

[0055]Therefore, the presence of such a receptor on the kidney cells isolated from healthy subjects has been demonstrated on the kidney cells isolated from patients suffering from ADPKD and on the ciPTEC-PC1KO cells. Furthermore, the location of the CaSR receptor has been detected at the level of the plasmatic membrane (FIG. 3) through ...

example 3

[0056]Increase of the Intracellular Calcium Levels Following the Treatment with Calciomimetics

[0057]Three types of the aforementioned cellular lines have been treated with 10 μM calciomimetic tecalcet, and the result is that the ciPTEC-PC1Pt cells, isolated from patients suffering from the polycystic kidney disease, respond similarly to the ciPTECwt cells to the stimulation with the calciomimetic, thus leading to an increase of intracellular calcium levels (FIG. 4). Such intracellular calcium levels, in the present example, have been detected thanks to the colorant Fura 2 that is sensitive to calcium. Therefore, it has been demonstrated that the calciomimetic tecalcet exerts a positive action on one of the alterations present in the polycystic kidney disease, i.e. the decrease of intracellular calcium.

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Abstract

Combination of antagonists of the vasopressin receptor and calciomimetics and composition comprising it, and its use for the prevention and/or treatment of polycystic kidney.

Description

TECHNICAL FIELD[0001]The polycystic kidney disease, known as polycystic kidney, is a genetic disorder of cystic type of which an autosomal dominant form, more common and typical in the adult, and a recessive autosomal form, more rare and present in the childhood, exist. In particular, the autosomal dominant form (ADPKD) is the most common lethal genetic disease and is the first cause of kidney failure worldwide.[0002]The polycystic kidney disease is caused by mutations in the PDK1 or PDK2 genes encoding for polycystin 1 (PC1) and polycystin 2 (PC2), respectively. PC1 interacts with PC2 to form a multifunctional complex, i.e. a channel, regulating the passage of intracellular calcium. The calcium ion is an important messenger that, when entering the cell or when it is released by the intracellular deposits, triggers a number of cellular changes. When PC1 or PC2 are mutated, such a channel is not adequately operating and the signal induced by the calcium is altered. All of this transl...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/55A61K31/137
CPCA61K31/55A61K31/137A61K45/06A61K31/135A61P13/12A61K2300/00
Inventor VALENTI, GIOVANNATAMMA, GRAZIADI MISE, ANNARITARANIERI, MARIANNA
Owner UNIV DEGLI STUDI DI BARI
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